N-chloro-aliphatic - n&#39;-(5-nitrothiazolyl)-ureas and cyclized compounds thereof



United States Patent 3,503,989 N-CHLORO-ALIPHATIC N-(-NITROTHIAZOLYL)-UREAS AND CYCLIZED COMPOUNDS THEREOF Paul Schmidt, Therwil, Max Wilhelm,Allschwil, and Kurt Eichenberger, Therwil, Switzerland, assignors toCiba Corporation, New York, N.Y., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No. 564,536, July 12, 1966. Thisapplication Nov. 15, 1966, Ser. No. 594,403

Claims priority, application Switzerland, May 30, 1962, 6,604/62; Apr.23, 1963, 5,056/63; Aug. 30, 1963, 10,800/63; Apr. 24, 1964, 5,395/64;July 8, 1964, 8,961/ 64; Sept. 3, 1964, 11,534/ 64; Mar. 3, 1965,2,949/65; Mar. 31, 1965, 4,423/65; July 20, 1965, 10,198/ 65 The portionof the term of the patent subsequent to Apr. 13, 1982, has beendisclaimed Int. Cl. C07d 91/34 U.S. Cl. 260-3068 6 Claims ABSTRACT OFTHE DISCLOSURE Antiparasitic and antibacterial2-ox0-1,3-diaza-cycloalkanes of the formula 2 TN/ NR H o in which Trepresents a 5-nitrothiazolyl-2-radical; Z stands for a lower alkyleneradical which separates the two nitrogen atoms by 2 to 5, preferably by3 or 4 but above all by 2, carbon atoms and which may be substituted byone or several, possily substituted, hydrocarbon radicals, and Rrepresents a hydrogen atom, an acyl radical or an unsubstituted orsubstituted hydrocarbon radical of aliphatic character, above all alower alkyl radical which is unsubstituted or substituted by a hydroxylgroup or by a free or substituted amino group, or a lower alkenyl or anaraliphatic radical and, as the case may be, their salts prepared bycyclization of the corresponding N-chloro-aliphatic-N- 5 -nitrothiazoly1-ureas.

This is a continuation-in-part of our copending application Ser. No.564,536, filed July 12, 1966 (now U.S. Patent No. 3,298,914), which is acontinuation-in-part of Ser. No. 485,927, filed Sept. 8, 1965 (now U.S.Patent No. 3,299,069), which in turn is a continuation-inpart of Ser.No. 447,868, filed Apr. 13, 1965 (now abandoned), which in turn is acontinuation-in-part of our application Ser. No. 391,294, filed Aug. 21,1964 (now abandoned, which in turn is a continuation-in-part of ourapplication, Ser. No. 282,589, filed May 23, 1963 (now abandoned).

The present invention relates to new 2-ox0-1,3-diazacycloalkanes.Especially it concerns 2-oxo-1,3-diaza-cycloalkanes of the formula inwhich T represents a 5-nitrothiazolyl-2 radical; Z stands for a loweralkylene radical which separates the two nitrogen atoms by 2 to 5,preferably by 3 or 4 but above all by 2, carbon atoms and which may besubstituted by one or several, possibly substituted, hydrocarbonradicals, and R represents a hydrogen atom, an acyl radical or anunsubstituted or substituted hydrocarbon radical of aliphatic character,above all a lower alkyl radical which is unsubstituted or substituted bya hydroxyl group or by a free or substituted amino group, or a loweralkenyl or an araliphatic radical and, as the case may be, their salts.

Particularly suitable as hydrocarbon radicals are lower alkyl, loweralkenyl, phenyl and phenyl-lower alkyl radicals such as benzylorphenylethyl radicals. These phenyl or phenyl-lower alkyl groups may besubstituted especially by lower alkyl groups, lower alkoxy groups suchas methoxy, ethoxy, propoxy or butoxy groups, or halogen atoms such aschlorine or bromine, trifluoromethyl groups or nitro groups.

In the foregoing and following lower alkyl radicals are preferably thosewhich contain up to 5 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl or pentyl groups. Lower alkenyl radicals areabove all allyl or methallyl radicals. As araliphatic radicals there maybe mentioned above all phenyl-lower alkyl groups, such as benzyl,1-phenylethyl or 2-phenylethyl radicals. The araliphatic radicals may besubstituted on the carbon atoms, especially on the aryl radicals byhalogen atoms such as chlorine or bromine, the pseudohalogentrifiuoromethyl, lower alkyls such as methyl or ethyl, by lower alkoxygroups such as methoxy, ethoxy or methylenedioxy or by nitro groups.

Substituted amino groups are monosubstituted or preferably disubstitutedamino groups, and the substituents may be above all lower alkyl, loweralkenyl, lower cycloalkyl radicals, or alkylene, mono-axaormono-aza-alkylene radicals having from 4 to 8 carbon atoms. There may bementioned, for example, monoor di-lower alkyl amino groups such asmethylamino, ethylamino, dimethylamino, diethylamino, dipropylamino,cyclohexylamino, methylcyclohexylamino, ethyl-cyclopentylamim,diallylamino, allyl-ethylamino or methallylamino groups, pyrrolidino,piperidino, morpholino, hexa or heptamethyleneamino, piperazino, N-loweralkyl piperazino or N-(hydroxy-lower a1kyl)-piperazino groups such asN-methylpiperazino or N-hydroxyethyl-piperazino groups.

If the radical R represents a substituted lower alkyl radical it standsmore especially for a hydroxyor tertiary amino-ethyl or -propyl radical,above all it represents a hydroxymethyl or a tertiary aminomethyl group.

Particularly suitable acyl radicals are those of carboxylic acids, inthe first place the acyl radicals of aliphatic carboxylic acids, such aslower alkanoic acids, for example propionic, butyric, trimethylacetic orvaleric acid or above all acetic acid, or of substituted lower alkanoicacids, such as halogen-lower alkanoic acids, for example monoordichloro-acetic acid or trifluoracetic acid. As further suitable acylradicals there may be mentioned the radicals of aromatic or araliphaticcarboxylic acids, such as those of benzoic acids or phenyl-loweralkaneor -alkene acids, for example phenylacetic acids, phenylpropionicacids, or cinnamic acids; also the acyl radicals of heterocycliccarboxylic acids, for example of pyridine-, furanor thiophene-carboxylicacids. The aromatic or heterocyclic rings of these carboxylic acids mayalso be substituted, for example by halogen, lower alkoxy, lower alkyl,trifiuoromethyl, nitro or amino groups.

The new compounds may be further substituted, more especially in the4-position of the thiazole ring, for example, by lower alkyl radicals,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl,lower alkenyl radicals such as allyl or methally, or by phenyl groups,and the phenyl radicals themselves may likewise be substituted, forexample as indicated above for the phenyl groups.

The radical Z is especially an unsubstituted ethylene- (1,2)-radical oran ethylene-(l,2)-radical substituted by lower alkyl radicals, or apropylene-(1,2), butylene-(l,4), or pentylene-( 1,5) radical which maybe substituted by lower alkyl radicals.

The new compounds possess valuable pharmacological, especiallyantiparasitic and antibacterial properties. They are primarily suitablefor the treatment of protozoic and helminthic conditions, for example ininfested animals, for example mice, against Gram-negative bacteria, forexample Salmonella typhi or coli bacilli, such as Escherichia coli. Ashas been demonstrated by experiments on hamsters, for example, the newcompounds are particularly effective against trichomonades and amoebae,and for example in mice and sheep against schistosomes. The newcompounds also act against coccidia. Accordingly, the new compounds maybe used as antiparasitic and antibacterial agents. They are especiallysuitable for the treatment of diseases caused by the pathogensmentioned. The new compounds are also valuable intermediates for themanufacture of other useful substances.

Especially valuable are the compounds of the formula in which R standsfor the radical of the formula(CH H and m and n each stands for aninteger from to and alk for a straight or branched lower alkyleneradical separating the two nitrogen atoms by 2 to 5 carbon atoms, thecompounds of the above mentioned Formula II in which n and alk have themeanings given above and R represents a hydroxy-lower alkyl radical,especially the hydroxymethyl radical, the compounds of the abovementioned Formula II in which n and alk have the meanings given above, Rstands for a di-lower alkyl-amino-lower alkyl radical, especially adi-lower alkyl-amino-methyl radical, and their acid addition salts, andthe compounds of the Formula II in which n and alk have the meaningsgiven above and R stands for lower alkanoyl.

Especially preferred groups of compounds are those of the formula .N CH

2 n OzNls N N-R III in which p stands for an integer from 2 to 4 and Rfor a hydrogen atom, those of Formula III in which F has the meaninggiven and R stands for a hydroxy-lower alkyl radical, especially for thehydroxymethyl radical, those of the Formula III in which I has themeaning given and R represents a di-lower alkyl-amino-lower alkylradical, especially a di-lower alkyl-aminomethyl radical, and their acidaddition salts, and the compounds of For mula III in which p has themeaning given and R stands for a lower alkanoyl radical, such as theacetyl radical.

A specially good action against amoebae and schistosomes exert the1-[5-nitro-thiazolyl-(2)]-2-oxotetrahydro-imidazole, the 1-[S-nitrothiazolyl- (2) -2-oxohexahydropyrimidine and the 1-[5-nitrothiazolyl-(2)]-2-oxo-3- acetyl-tetrahydroimidazole.

The new compounds are manufactured by known methods.

For example, the new compounds are obtained when a compounds of thegeneral formula where T, Z and R have the above meanings, is subjectedto intramolecular 9ndensation accompanied by elimination of hydrochloricacid and, if desired, in a compound so obtained theradical R isintroduced into the 3-posi tion of the diaza-cycloalkane ring.

The intramolecular condensation (cyclisation) is preferably performed byheating, advantageously in the presence of a polar solvent, above allwater, and/or in the presence of a condensing agent, especially a basiccondensing agent such as an alkali metal acetate Or carbonate, ifdesired in a suitable solvent, such as an acid amide, for exampledimethylformamide.

According to another process for the manufacture of the new compounds acompound of the general formula where R and Z have the above meaningsand T is a thiazolyl-2 radical which is unsubstituted in position 5- isnitrated. Nitration is carried out in the manner known in thiazolechemistry, for example by treatment with a mixture of concentratedsulfuric and concentrated nitric acid or with the mixed anhydride ofnitric acid and a carboxylic acid, such as acetic acid. Any phenylgroups present may be nitrated at the same time.

The introduction of a substituent R into a compound in which R is ahydrogen atom is performed in the known manner, for example in themanufacture of compounds in which the substituent R is an unsubstitutedor substituted hydrocarbon radical of aliphatic character, such as alower alkyl radical which is unsubstituted or substituted by a hydroxylgroup or by a free or substituted amino group, or a lower alkenyl or anaraliphatic radical and in which the substituent R contains no hydroxyl0r amino groups or in which any hydroxyl or amino groups present in Rare separated from the cyclic nitrogen atom by at least 2 carbon atoms,by reaction with a halide of the formula RX in which R has the abovemeaning and X represents a halogen atom, such as a chlorine atom. Ifdesired, this operation is performed with a metal salt such as an alkalimetal salt of the 3-unsubstituted 2-oxotetrahydro-imidazole, or in thepresence of a basic condensing agent, especially a condensing agentcapable of forming metal salts, such as an amide, hydride, hydrocarbon,hydroxide, alcoholate or carbonate of an alkali metal.

Compounds in which R is a methyl radical that carries a hydroxyl groupor a free or substituted amino group, especially a hydroxymethyl orsecondary or tertiary aminomethyl radical are obtained by reaction withformaldehyde, if desired or required in the presence of ammonia or of anamine.

Introduction of the hydroxymethyl group is achieved by a simple reactionwith formaldehyde, if desired in the form of a formaldehyde donor, suchas trioxymethylene or paraformaldehyde, advantageous y in the presenceof a basic condensing agent, such as an alkali metal hydroxide orcarbonate, or of a tertiary amine or quaternary ammonium hydroxide, suchas triethylamine or benzyltrimethyl ammonium hydroxide.

The aminomethyl group is advantageously introduced by the Mannichreaction, for example with formaldehyde, with the use of a salt ofammonia or of an amine. Also in this case the formaldehyde may be usedin the form of a donor, such as trioxymethylene or paraformaldehyde, ifdesired in the presence of an acid.

The introduction of an acyl radical in 3-position of a 3-unsubstituted1-[5-nitrothiazolyl]-1,3 diazacycloalkane is performed e.g. by reactionof a compound of the formula in which T and Z have the meanings givenabove, with reactive derivatives of acids, above all the halides, suchas chlorides or bromides, or their anhydrides. It is adantageous to usea condensing agent. Thus bases such as pyridine or acylate ions promotethe reaction of the acid anhydrides, and bases, such as pyridine oralkali, for example sodium carbonate, promote the reaction of the acidhalides.

The above-mentioned reactions are performed in the usual manner.

Depending on the reaction conditions and starting materials used, thefina-l products having substituted or unsubstituted amino groups areobtained in the free form or in the form of their salts which arelikewise included in the present invention. A resulting amine can beconverted into a salt thereof in the usual manner by reaction with anorganic or inorganic acid, especially one that is suitable for theformation of therapeutically acceptable salts. On the other hand, aresulting salt can be converted into the free compound in the usualmanner, for examp e by treatment with a basic agent or ion exchangeresin. Acids, suitable for the formation of therapeutically acceptablesalts, are for instance hydrohalic, sulfuric or phosphoric acids, nitricor perchloric acid; alicyclic, aromatic or heterocyclic carboxylic orsulfonic acids such as formic, acetic, propionic, succinic, glycollic,lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic orpyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic,para-hydroxybenzoic, salicyclic, para-aminosalicyclic or embonic acid,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonicacid, halogenbenzenesulfonic, toluenesulfoni-c, naphthalenesulfonicacids or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, for example, the picrates,can also be used for purification of the amines obtained; the amines areconverted into salts, the salts are separated and the amines areliberated from the salts. In view of the close relationship between thefree amino-compounds and the amino-compound in the form of a saltthereof. whenever a free amine is referred to in this context, acorresponding salt is also intended provided such is possible or appicable under the circumstances.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which a startingmaterial is formed under the reaction conditions or is used in the formof a salt.

It is advantageous to use starting materials that give rise to the finalproducts described above as being particularly valuable.

The starting materials used are known or, insofar as they are new, theycan be prepared by known methods.

The new compounds may be used for example in the form of pharmaceuticalpreparations which contain them in the free form or in the form of theirsalts in conjunction or admixture with an organic or inorganic solid oriquid pharmaceutical excipient suitable for enteral, parenteral or localadministration. Suitable excipients are substances that do not reactwith the new compounds, for example water, gelatine, lactose, starches,magnesium stearate, talcum, vegetable oils, benzyl alcohol, gums,polyalkyleneglycols, white petroleum jelly, cholesterol or other knownmedicinal excipient. The pharmaceutical preparations may be, forexample, tablets, dragees, ointments or creams, or in liquid fromsolutions, suspensions or emulsions. They may be sterilized and/orcontain assistants such as preserving stabilizing, wetting oremulsifying agents, salts for regulating the osmotic pressure, orbuffers. They may also contain further therapeutically valuablesubstances, such as for example 2-sulfanilamido- 6-chloropyrazine.

The above-mentioned products may also be used in conjunction withconventional animal fodders or vehicles as fodders or additives tofodders in animal husbandry.

The following examples illustrate the invention.

EXAMPLE 1 25 grams of N-(2-ch orethyl)-N'-[5 nitrothiazolyl- (2)]-ureain 1 liter of Water are stirred and heated for 7 hours to the boil. Theprecipitate formed is filtered off and recrystallized fromdimethylformamide+methanol, to yield I-[S-nitrothiazolyl (2) 2oxo-tetrahydroimidazole of the formula N p l CH2CH O2N-L 1 111 C H O inyellow crystals metling at 259-260 C.

The urea used as starting material may be prepared as follows:

A solution of 25 grams of 2-amino-5-nitrothiazole and 50 grams of2-chlorethyl isocyanate in 250 cc. of tetrahydrofuran is heated in aclosed vessel for 16 hours at to C. After cooling, cc. oftetrahydrofuran are evaporated, the precipitate formed is suctioned olfand thoroughly washed with warm isopropyl ether, to yieldN-(Z-chlorethyl)-N-[S-nitrothiazolyl-(Z)]-urea in crystals melting at140 C. with decomposition.

EXAMPLE 2 2.5 g. of N-(2-chloropropyl)-N[S-nitro-thiazolyl- (2)]-ureaare boiled for 4 hours in a solution of 14 g. of sodium acetate in 200cc. of water. The precipitate which forms is filtered off andrecrystallized from dimethyl formamide-l-ethanol. There is thus obtainedthe 1-[5- nitrothiazolyl-(2) 1-2-oxo-S-methyl-tetrahydroirnidazole ofthe formula l F+H--(I3H2 OzN J N NH in the form of yellow crystals ofmelting point 237- 238 C.

The urea used as starting material can be prepared as follows:

To a suspension of 5 g. of potassium carbonate in 50 cc. of acetone areadded 14.5 g. of Z-amino-S-nitrothiazole and 12 g. of2-chloro-propylisocyanate. The mixture is stirred at the boilingtemperature for 3 hours and the precipitate that forms is filtered offand washed with water. The filter residue is recrystallized fromethanol-f-water. There is obtained N-(2-chloro-propyl)-N'-[5-nitrothiazolyl-(2)]-urea in the form of crystals which melt at -172 C.

EXAMPLE 3 22 g. of N-[2-chloro-butyl-(3)]-N-[5-nitro-thiazolyl-(2)]-urea are heated at 100 C. for 10 minutes with 13 g. of sodiumacetate in 40 cc. of dimethyl formamide. There are then added 200 cc. ofwater, and the precipitate which forms is filtered oif. The filterresidue is washed with 1 N-sodium hydroxide solution and, for furtherpurification recrystallized from dimethyl formamide+ ethanol. There isobtained the 1-[5-nitro-thiazolyl-(2)]-2-oxo-4:S-dimethyl-tetrahydroimidazole of the formula 7 in the form ofyellow crystals of melting point 242 243 C.

The urea used as starting material is prepared as follows:

14 g. of Z-amino-S-nitrothiazole are heated to 100 C. for four hourswith 12 g. of 2-chloro-butyl-(3)-iso-cyanate in 100 cc. of absolutetetrahydrofuran. The solution is then evaporated to dryness underreduced pressure. The residue is recrystallized from ethanol to obtainN- [2-chloro-buty1- (3 ]N'- [.S-nitro-thiazolyl- (2) ]-urea in the formof crystals melting at 195 C.

EXAMPLE 4 15 g. of 1-[4-phenyl-thiazolyl-(2)]-[2-oXo-tetrahydroimidazoleare introduced into 50 cc. of concentrated sulfuric acid in such mannerthat the temperature does not rise above 10 C. After that, 7 g. ofconcentrated nitric acid are slowly added dropwise, and the mixturestirred at room temperature for hours. The reaction mixture is poured onto ice. A precipitate forms which is filtered off and recrystallizedfrom dimethyl formamide. The 1-[4- para nitrophenyl 5nitro-thiazolyl-(Z) ]-2-oxo-tetrahydroimidazole of the formula isobtained in the form of yellow crystals of melting point 286-288 C.

The 1- [4-phenyl-thiazolyl- 2) ]-2-oxo-tetrahydroimidazole used asstarting material can be prepared as follows:

10 g. of 2-chloro-ethyl-isocyanate are added to 10 g. of2-amino-4-phenyl-thiazole in 50 cc. of dimethyl formamide and themixture heated at 80 C. for 2 hours. The mixture is then cooled treatedwith water, and the precipitate that forms recrystallized from ethanol.There is thus obtained N [4 phenyl-thiazolyl-(Z)]-N'-(2-chlorethyl)-urea of melting point l73174 C.

10 g. of the urea are heated at 110 C. for 30 minutes with 6 g. ofsodium acetate in 100 cc. of dimethyl formamide. There are then added300 cc. of water. The precipitate which forms is recrystallized fromaqueous dimethyl formamide to obtain 1-[4-phenyl-thiazolyl-(2)]-2-oxo-tetrahydro-imidazole in the form of white crystals melting at250252 C.

EXAMPLE 5 A mixture of 16.0 g. of 2-amino-4-methyl-S- nitrothia'zole,11.0 g. of fi-chloroethylisocyanate, 5.0 g. of potassium carbonate, and150 cc. of acetone is stirred while being boiled for 17 hours,N-(Z-chloroethyl)-N-[4-methyl-S-nitro-thiazonyl (2)] urea beinginterrnediately formed and partly cyclized. The batch is then cooled,treated with 200 cc. of water, and the resulting precipitate, which is amixture of N-(2-chloroethyl)-N'-[4- methyl-S-nitro-thiazolyl-(2)]-ureaand 1-[4-methyl 5- nitro-thiazolyl-(Z) ]-2-oxo-tetrahydro-imidazole, isfiltered off. The residue is introduced into 50 cc. of dimethylformamide and, after the addition of 10.0 g. of sodium acetate, heatedat 100 C. for 30 minutes. Water is then added and the resultingprecipitate recrystallized from dimethylformamide+ethanol.1-[41rnethyl-5-nitro-thiazolyl- (2)]-2-oxo-tetrahydro-imidazole of theformula EXAMPLE 6 10 grams ofI-[S-nitrothiazolyl-(Z)]-2-oxo-tetrahydroimidazole are dissolved in 40cc. of dimethylformamide. 50 cc. of a 30% formaldehyde solution in waterare then added followed by 0.5 cc. of an solution ofbenzyltrimethyl-ammoniumhydroxide in methanol. After the reactionmixture has been allowed to stand for 2 hours at room temperature,1-[5-nitrothiazolyl-(2)]-2-0xo-3-hydroxymethyl-tetrahydroimidazole ofthe formula N l t OzN s N\ /NCH2OH is precipitated by the addition ofwater. After recrystallization from a mixture of dimethylformamide andwater, the compound melts at 185 to 187 C.

EXAMPLE 7 10 grams of1-[5-nitrothiazolyl-(2)]-2-oxo-tetrahydroimidazole, 1.4 grams ofparaformaldehyde and 3.8 grams of dimethylaminehydrochloride are heatedfor 4 hours at 120 C. in cc. of dimethylformamide. After cooling thereaction mixture, a precipitate is obtained that is purified byrecrystallization from highly dilute hydrochloric acid.1-[5-nitrothiazolyl-(2) ]-2-oxo 3dimethylaminomethyl-tetrahydroimidazole-hydrochloride of the formula N II oH.- JH2 OZN N NCH2N(CHa)2-HO1 o it is obtained in the form ofcrystals melting at 278 to EXAMPLE 8 CH3 N t OzN N NCH2OH in the form ofyellow crystals melting at 153-154 C.

EXAMPLE 9 A mixture of 10 grams of 1-[5-nitrothiazolyl-(2)]-2-oxo-tetrahydroimidazole, 1.4 grams of paraformaldehyde and 3.5 grams ofmethylamine hydrochloride in 80 ml. of dimethylformamide is heated for 3hours at C. with stirring. After cooling the reaction mixture, theprecipitate is filtered and recrystallized fromdimethylfo-rmamide-f-ethanol. 1- [S-nitrothiazolyl-(Z)]-2-oxo-3-methylaminomethyl-tetrahydroimidazole hydrochloride of theformula N I OQN N N-C HzNH-CH .H 01

is obtained in the form of crytals melting at 260 C. with decomposition.

9 EXAMPLE 1.2 grams of sodium hydride are added to 100 ml. of dimethylsulfoxide and the whole is heated -for 2 hours at 70 C. with stirring.The reaction mixture is cooled to room temperature, 10 grams of1-[5-nitrothiazolyl- (2)]-2-oxo-tetrahydroimidazole in 50 ml. ofdimethyl sulfoxide are added dropwise and the batch stirred for 30minutes. 8.0 grams of diethylaminoethyl chloride are then addeddropwise. After stirring for 4 hours at 20-25 C. excess sodium hydrideis destroyed by the addition of a little ethanol. On the addition ofwater, a brown precipitate settles which is filtered and dissolved in 2N acetic acid. The solution is treated with active carbon, filtered andrendered neutral by the addition of sodium carbonate. 1 [5nitrothiazolyl-(2)]-2-oxo-3-(fl-dimethylaminoethyl)-tetrahydroimidazoleof the formula precipitates in the form of crystals melting at 140-141C.

EXAMPLE 11 2 drops of an 80% solution ofbenzyltrimethylammoniumhydroxide in methanol and then 30 ml. of aformaldehyde solution of 30% strength are added to a solution of 8.0grams of I-[S-nitrothiazolyl-(Z)]-2-oxo-5-methyltetrahydroimidazole in30 ml. of dimethylformamide at 80 C. The batch is cooled to roomtemperature and after 8 hours 200 ml. of water are added. A precipitateof 1-[5- nitrothiazolyl (2)] 2oxo-3-hydroxymethyl-5-methyltetrahydroimidazole of the formula settleswhich, after recrystallization from methanol, melts at 170-174 C.

, EXAMPLE 12 13.0 g. of N-[5-nitrothiazolyl-(2)] -N'(3-ch1oropropyl)-urea are added to a solution of 7.0 g. of sodiumacetate in 150 cc. of water and stirred for 3 hours at 90 C. Theinsoluble share is filtered 01f and recrystallized fromdimethylformamide, to yield crystalline1-[5-nitrothiazolyl-(2)]-2-oxo-hexahydropyrimidine of the formula To awarm solution of 7.0 g. of 1-[5-nitro-5-thiazolyl-(2)]-2-oxo-hexahydropyrimidine in 30 ml. of dimethylformamide are added2 drops of a 50% ethanolic solution of benzyltrimethylammoniumhydroxideand 50 ml. of 40% formalin. After 1 hour the mixture is treated with 10200 ml. of water and recrystallized from methanol to obtain crystals ofI-[S-nitrothiazolyl-(Z)]-3-hydroxymethyl- 2-oxo-hexahydropyrimidine ofthe formula which melt at 158 to 160 C.

EXAMPLE 14 A mixture of 10 g. ofl-[5-nitrothiazolyl-(2)]-2-oxotetrahydroimidazole and 50 ml. of aceticanhydride is boiled for 4 hours and then allowed to cool to roomtemperature. The precipitate formed is filtered off and recrystallizedfrom dimethyl-formamide+ethanol, to yield 1 [5nitrothiazolyl-(2)]-2-oxo-3-acetyl-tetrahydroimidazole of the formula -Nl CIIHZ--(IJHZ OgN- S N\ /N-CCH3 in yellow crystals melting at 163 to166 C.

EXAMPLE 15 The new compounds can be used in the form of phar maceuticalpreparations, the daily dose being 0.1 to 10 mg. per kg. of body weight.Administration can be carried out, for example, in the form of capsulescontaining the desired amount of the active substance, above all 1 [5-nitrothiazolyl- (2) -2-oxo-hexahydropyrimidine.

For use as additives to animal fodder, for example chickenfeed, the newcompounds, especially 1-[5-nitrothiazolyl-(2)]-2-oxo-hexahydropyrimidinecan be mixed, for example, with cerelose (content of active compounds,for example, 0.1 to 1%, preferably 0.5%). This preliminary mix can beadded to the fodder in the usual manner, advantageously so that themixture contains about 0.01% of the pyrimidine derivative.

EXAMPLE 16 Tablets containing 500 mg. of 1-[5-nitrothiazolyl-(2)2-oxo-tetrahydroimidazole may be prepared with the followingingredients:

Per tablet, mg. 1- [5 -nitrothiazolyl- 2) ]-2-oxo-tetrahydro Method Halfof the wheat starch is pasted with four times the quantity of water on awaterbath. I-[S-nitrothiazolyl- (2)]-2-oxo-tetrahydroimidazole ishomogeneously mixed with the remaining starch, then kneaded with thepaste and with a sutficient quantity of water to form a plastic mass.The colloidal silicic acid with hydrolysed starchis then worked inportions.

The plastic mass is passed through a sieve having a 4-5 mm. mesh anddried at 45 C. The dried granulate is passed through a sieve of 0.8-1.4mm. mesh and the remaining disintegrating and lubricating agents arethen added. After further homogenisation tablets having a di ameter of11.5 mm. and weighing 625 mg. are compressed in the conventional manner.

In the same manner, tablets containing 1-[5-nitrothiaZolyl-(2)] 2oxo-3-(hydroxymethyl)-tetrahydroimidazole can be prepared.

EXAMPLE 17 7.8 g. of B-chloro-tertiary butylisocyanate in 15 ml. ofacetone are added dropwise to 9.0 g. of 2-amino-5-nitro thiazole and 5.0g. of anhydrous potassium carbonate in 60 ml. of acetone, and themixture heated for 90' minutes at 45 C. 100ml. of 2 N-hydrochloric acidare then added. The precipitate which forms is dissolved in 40 ml. ofdimethyl formamide and the solution, after addition of 12.0 g. of sodiumacetate, heated at 100 C. for 30 minutes. After cooling to roomtemperature, 100 ml. of water are added, and the resulting precipitaterecrystallized from alcohol. There is obtained the1-[5-nitro-thiazolyl(2)1- 2-oxo-4,4-dimethyl-tetrahydro-imidazole of theformula in the form of yellow crystals melting at 221224 C.

The ,B-chloro-tertiary butylisocyanate (boiling at 53- 56" C. under apressure of 22 mm. Hg) used as starting material can be obtained fromB-hydroxy-tertiary butylamine by reaction with thionyl chloride to formthe ,3- chloro-tertiary butylamine hydrochloride, and treatment of thelatter with phosgene by the method of W. Siefken, Ann. 562, 75 et seq.(1949).

EXAMPLE 18 2.5 g. of 1-[5-nitro-thiazolyl-(2)]-2-oxo-hexahydro- Apyrimidine, 0.33 g. of paraformaldehyde, and 0.9 g. of dimethylaminehydrochloride in 25 cc. of dimethyl formamide are heated at 100 C. for 2hours. The precipitate is filtered off with suction and recrystallizedfrom 2 N-hydrochloric acid. The 1-[5-nitro-thiazolyl-(2)]-2-oxo-3-(dimethylaminomethyl) -hexahydro-pyrimidine hydrochloride of the formulaN /Cg2 l 111. CH 011 N N N-CH N .HCl

melt at 170-173 C.

EXAMPLE 20 10.0 g. ofI-[S-nitro-thiazolyl-(Z)]-2-oxo-tetrahydroimidazole are stirred andheated at 150 C. for 4 hours with 20.0 g. of benzoic anhydride. Thereaction mixture is then recrystallized from dimethyl formamide toobtain 12 1-[5-nitro-thiazolyl-(2)]-2-oxo 3 benzoyl tetrahydroimidazoleof the formula in the form of yellow crystals melting at 273 C.

EXAMPLE 21 10.0 g. of 1-[4-methyl-S-nitrothiazolyl-(2)]-2-oxo-tetrahydro-imidazole are heated at the boil for 4 hours with 50ml. of acetic anhydride. After cooling, a precipitate forms which isrecrystallized from dioxan. There is obtained in this manner1-[4-methyl-S-nitro-thiazolyl-(2)]- 2-oxo-3-acetyltetrahydro-imidazoleof the formula which melts at 213215 C.

EXAMPLE 22 At 10 C., 20 ml. of concentrated nitric acid are stirred intoa solution of 5.0 g. of 1-[thiazolyl-(2)]-3-acetyl-2-oxo-tetrahydro-imidazole in 50 ml. of concentrated sulfuric acid. Thebatch is stirred for 3 hours at 10 C., then poured on ice. Theprecipitate which forms is filtered off and recrystallized frommethanol-i-dimethylformamide. There is obtained in this manner the1-[5-nitrothiazolyl-(2)] 2 oxo-3-acetyl-tetrahydro-imidazole of meltingpoint 166 C. which is identical with the product described in Example14.

The 1 [thiazolyl-(Z)]-3-acetyl-2-oxo-tetrahydro-imidzaole used asstarting material can be prepared by acetylating1-[thiazolyl-(2)]-2-oxo-tetrahydro-imidazole with acetic anhydride. Thecompound melts at 185 C.

EXAMPLE 23 in the form of yellow crystals of melting point 245- 247 C.

EXAMPLE 24 2.0 g. of 1-[5-nitro-thiazolyl-(2)]-2-oxo-hexahydropyrimidinein 5.0 ml. of dimethylformamide are heated at C. for 2 hours with 5.0ml. of acetic anhydride. After cooling, 50* ml. of water are added, andthe batch extracted with 50 ml. of methylene chloride. The methylenechloride layer is separated and evaporated under vacuum. There remains acrystalline residue of l-[5-nitro- 13thiazolyl-(2)]-2-oxo-3-acetylhexahydropyrimidine of the formula N-O-OHBwhich after being recrystallized from a mixture of methylene chlorideand petroleum ether melts at 220-230 C.

EXAMPLE 25 10.0 g. of 1 [-nitrothiazolyl (2)] oxo-tetrahydroimidazoleare heated at 150 C. for 4 hours wtih 50.0 g. of butyric anhydride.After cooling, ethanol is added and the batch filtered. The filtrate isevaporated, and the residue recrystallized from aqueous ethanol. The1-[5- nitrothiazolyl (2) ]-2-oxo-3-butyry1-tetrahydro-imidazole of theformula is obtained in the form of yellow crystals melting at 143- 145C.

EXAMPLE 26 mula OzNl

N I CH2CH2 02115 in the form of yellow crystals melting at 140-141 C.

The 1 [thiazolyl-(2)]-2-oxo-3-(B-diethylaminoethyl) tetrahydro-imidazoleused as starting material is prepared as follows:

17 g. of 1 [thiazolyl-(2)]-2-oxo-tetrahydro-imidazole are added to asuspension of 2.4 g. of sodium hydride in 200 ml. of toluene, and thewhole is heated for 2 hours at 90 C. The reaction mixture is cooled to50 C., and 15 g. of fi-diethylamino-ethyl chloride are added dropwise.The batch is heated for 4 hours at 90 C., 50 ml. of a1- cohol are thenadded at room temperature, the reaction mixture evaporated in vacuo, andthe residue ditsilled in a high vacuum 1 [thiazolyl(2)]-2-oxo-3-(B-diethylaminoethyl)-tetrahydroimidazole distills at163-165 C. under 0.1 mm. pressure.

EXAMPLE 27 1.6 g. of concentrated nitric acid are added to a solution of4.0 g. of 1 [thiazolyl-(2)]-3-methyl-2-oxo-tetrahydro-imidazole in 20ml. of concentrated sulfuric acid and the mixture stirred for 4 hours atroom temperature. The reaction mixture is poured on ice. The precipitatewhich forms is filtered off and washed with acetone. There is obtainedin this manner 1 [5-nitrothiazolyl-(2)]-3-methyl-Z-oxo-tetrahydro-imidazole-(2) of the formula which melts at239-241 C.

The 1 [thiazolyl-(2)]-3-methyl-2-oxo-tetrahydroimidazole may be preparedas follows:

To a solution of 15.0 g. of Z-amino-thiazole in 150 ml. of boiling etherare slowly added dropwise 16.0 g. of B- chlorethylisocyanate. When themixture is allowed to stand for a while, the N [thiazolyl-(2)]-N-(fi-chlorethyl)- urea crystallizes. After being recrystallized fromalcohol it melts at 142143 C.

10 g. of the chlorethyl urea are boiled for 4 hours with 300 ml. ofwater. The precipitate which forms is filtered OE and recrystallizedfrom dimethylformamide-l-methanol. There is obtained1-[thiazolyl-(2)]-2-oxo-tetrahydroimidazole in the form of whitecrystals of melting point 209-210 C.

10.0 g. of l-[thiazolyl-(Z)]-2-oxo-tetrahydro-imidazole are added to asuspension of 1.5 g. of sodium hydride in 100 ml. of toluene and themixture stirred while being heated at C. for 1 hour. There are thenslowly added 8.0 g. of dimethyl sulfate, and, after 4 hours, the batchcooled to room temperature and filtered. The filtrate is evaporatedunder reduced pressure. The residue is recrystallized from methanol and1-[thiazolyl-(2)]-3-methyl-2- oxo-tetrahydroimidazole obtained in theform of crystals melting at 128-130" C.

EXAMPLE 28 Chick starter containing 0.005% of compound I and 0.0075 ofcompound II as coccidiostatic ingredients:

I: 1-[5 nitrothiazolyl(2)] 2 oxo-tetrahydroimidazole 50.0 II:2-sulfaniliamido-6-chloropyrazine 75.0

Formula: Pounds Corn meal 1103.0 Soybean meal, 44% protein 660.0 Alfalfameal 30.0 Dicalcium phosphate 40.0 Limestone meal 10.0 Salt 5.0 Fishmeal, 60% protein 40.0 Stabilized fat 60.0 Dried whey 40.0 Manganesesulfate 05 Zinc oxide 0.3 d,l-Methionine 1.5 Vitamin premix 10.0

10 lb. of the vitamin composition contain: 16,000,000 I.U. vit. A,1,000,000 I.U. vit. D 5,000 I.U. vit. E acetate, 6 g. vit. K 6 mg. vit.B 3 g. riboflavin, 30 g. niacin, 5 g. calcium pantothenate and g.ethoxyquin, made up to 10 lb. wtih corn meal.

The compounds I and II are first premixed with a small amount (about 2lb.) of the feed mixture (which is supplied as such by themanufacturer). The premix is increased to about 50 lb. and thenthoroughly mixed with the main batch in a horizontal mixer.

EXAMPLE 29 A premix containing one percent of 1-[5-nitro-thiazolyl- (2)]-2-oxo-tetrahydroimidazole is prepared as follows (for 1000 g.):

Ingredients: G.

1-[5-nitro-thiazoly1-(2)] 2 oxo-tetrahydroimidazole 10.00 Sugar,confectioners 100.00 Soybean, feed, solvent extracted 890.00

The ingredients are thoroughly mixed in appropriate mixing equipment.,The premix is then added to the feed formula in desired quantities.

The feed formula is prepared as previously shown; the vitamin premix hasthe following ingredients:

Vitamin A'4,000,000 U.S.P. units d-Pantothenic acid-3,680.0 g.Riboflavin-40 g. Vitamin g.

Vitamin D -2,000,000 U.S.P. units Vitamin E2,500 I units whereas theMineral premix contains the following essential minerals:

Percent Manganese 6.00 Iodine 0.12 Iron 2.00 Copper 0.20 Zinc 2.00

Cobalt 0.02 Calcium 25.20

The premix is added to the above feed formula in an amount sufiicient toprovide concentrations of 0.5 g. and 1.0 g. of 1- [S-nitro-thiazolyl-(Z)]-2-oxo-tetrahydroimidazole per 1,000 g. of feed.

1 6 What is claimed is: 1. A compound of the formula in which R standsfor a member selected from the group consisting of hydrogen, loweralkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl,trifiuoromethyl-phenyl and nitrophenyl, and Z represents a memberselected from the group consisting of unsubstituted straight chainlower'alkylene containing 3 to 5 carbon atoms and straight chain loweralkylene containing 2 to 5 carbon atoms substituted by from one to twolower alkyl groups.

2. A compound as claimed in claim 1, said compound having the formula inwhich Z stands for a member selected from the group consisting ofethylene(l,2) which is substituted by at least one methyl radical, andpropylene(1,3).

3. A compound of claim 1, said compound being N-(2- chloropropyl) -N'-[5 -nitrothiazolyl- 2) ]-urea.

4. A compound of claim 1, said compound being N-[2- chlorobutyl- 3 -N'-[5 -nitrothiazo1yl-2 -urea.

5. A compound of claim 1, said compound being N-(3- chloropropyl)-N'-[5-nitrothiazolyl-( 2) ]-urea.

6. A compound of claim 1, said compound being N- (fl-chloro-tertiarybutyl -N- S-nitrothiazolyl- (2) ]-urea.

References Cited UNITED STATES PATENTS 7/1956 ONeill et al. 260-3063 4/1965 Schmidt et al 260'-306.8

OTHER REFERENCES Burger: Medicinal Chemistry, N.Y., 1960, p. 43.

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl.X.R.

CASE 5o82/1+2/535o/1+2/ 5 54/1-3/5517/cIP/ l+2/CONT./3 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,503,989 Dated March31, 1970 It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 35, change "possily" to read possibly line 5 after"abandoned" insert Column 2, line 68, change "methally" to readmethallyl Column 3, lines 70-71, the formula should read:

line 69, change "compounds" to read compound line 74, after "meanings"delete and insert Column 5, lines 3 change "adantageous" to readadvantageous line 69, change "from" to read form Column 7, line 9,before "N'" insert line 55,

change "thiazonyl" to read thiazolyl Column 9, line 15, change"dimethylaminoeth-" to read diethylaminoeth- Page 1 of 2.

- CASE 5o8 2/1+2/535o/1+2/ 545 +/1-3/5517/ IIP/ 1+2/coNT./3 UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,503,989Dated March 31, 1970 Inv nt PAUL SCHMIDT ET AL It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 11, lines M4 to &9, the middle of the formula should read:

Column 12, lines 5-9, the right hand side of the formula should read:

ll 0 line 54, after -(2)] insert -2 Column 13, line 13, change "230C" toread 223C line 6n, change "ditsilled" to read distilled Column 16, line31, after "nitrothiazolyl-" insert Signed and sealed this 30th day ofMarch 1971.

(SEAL) Attest:

EDWARD M.FLETCFER,J'R. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

